Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation

S. Bang, S. Yoo, T. J. Yang, H. Cho, Sun Wook Hwang

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE Sensory neuronal and epidermal transient receptor potential ion channels (TRPs) serve an important role as pain sensor molecules. While many natural and synthetic ligands for sensory TRPs have been identified, little is known about the endogenous activator for TRPV4. Recently, we reported that endogenous metabolites produced by the mevalonate pathway regulate the activities of sensory neuronal TRPs. Here, we show that dimethylallyl pyrophosphate (DMAPP), a substance produced by the same pathway is an activator of TRPV4. EXPERIMENTAL APPROACH We examined the effects of DMAPP on sensory TRPs using Ca 2+ imaging and whole-cell electrophysiology experiments with a heterologous expression system (HEK293T cells transfected with individual TRP channels), cultured sensory neurons and keratinocytes. We then evaluated nociceptive behavioural and inflammatory changes upon DMAPP administration in mice in vivo. KEY RESULTS In the HEK cell heterologous expression system, cultured sensory neurons and keratinocytes, μM concentrations of DMAPP activated TRPV4. Agonistic and antagonistic potencies of DMAPP for other sensory TRP channels were examined and activation of TRPV3 by camphor was found to be inhibited by DMAPP. In vivo assays, intraplantar injection of DMAPP acutely elicited nociceptive flinches that were prevented by pretreatment with TRPV4 blockers, indicating that DMAPP is a novel pain-producing molecule through TRPV4 activation. Further, DMAPP induced acute inflammation and noxious mechanical hypersensitivities in a TRPV4-dependent manner. CONCLUSIONS AND IMPLICATIONS Overall, we found a novel sensory TRP acting metabolite and suggest that its use may help to elucidate the physiological role of TRPV4 in nociception and associated inflammation.

Original languageEnglish
Pages (from-to)1433-1443
Number of pages11
JournalBritish Journal of Pharmacology
Volume166
Issue number4
DOIs
Publication statusPublished - 2012 Jun 1

Fingerprint

Sensory Receptor Cells
Keratinocytes
Inflammation
Transient Receptor Potential Channels
Camphor
diphosphoric acid
Pain
Mevalonic Acid
Nociception
Electrophysiology
Ion Channels
Hypersensitivity
Ligands
Injections

Keywords

  • dimethylallyl pyrophosphate
  • keratinocyte
  • pain
  • sensory neuron
  • TRPV4

ASJC Scopus subject areas

  • Pharmacology

Cite this

Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation. / Bang, S.; Yoo, S.; Yang, T. J.; Cho, H.; Hwang, Sun Wook.

In: British Journal of Pharmacology, Vol. 166, No. 4, 01.06.2012, p. 1433-1443.

Research output: Contribution to journalArticle

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